The matrix metalloprotease family of zinc endoproteinases includes interstitial (type 1) and neutrophil collagenase (MMP1 and MMP8), the stromelysins (also known as proteoglycanases or transins), fibroblast and polymorphonuclear leucocyte gelatinases (also known as collagen-IV-ases) and `pump-1` (putative metalloprotease 1, uterine metalloprotease). Accelerated breakdown of connective tissues by metalloprotease catalyzed resorption of extracellular matrix is a feature of many pathological conditions. Matrix metalloproteases are involved in connective tissue degradation of several inflammatory conditions where the breakdown of articular cartilage and bone leads to stiffness and immobility. Aberrant regulation of these enzymes has been implicated in pathologies such as rheumatoid arthritis. See Arthritis and Rheumatism, 20, 1231-1239 (1977). Interstitial collagenase and stromelysin have been found at elevated levels in the joints of many patients suffering from rheumatoid arthritis as shown by immunolocalization of collagenase at sites of erosion. See Arthritis and Rheumatism, 34, 1076-1105 (1991).
Matrix metalloproteases have also been implicated in the initiation of tumor metastisis/angiogenesis, and in the pathogenesis of demyelating diseases of the nervous system. See Nature, 284, 67-68, (1980), and J. Neurochem., 50, 688-694 (1988). Additionally, matrix metalloproteases may be involved in conditions such as arthropathy, dermatological conditions, bone resorption, osteopenias such as osteoporosis, hyperparathyroidism, cholesteatoma, osteoarthritis, periodontitis, gingivitis, dystrophic epidermolysis bullosa, corneal ulceration, multiple sclerosis, optic neuritis, neuromyelitis optica, diffuse and transitional sclerosis, and acute disseminated encephalomyelitis and demyelinating peripheral neuropathies including acute inflammatory demyelinating polyradiculoneuropathies [Landry-Guillain-Barre-Strohl syndrome for motor defects and analogous syndromes for sensory and autonomic (pandysautonomia) deficits].
The compounds of the present invention act as inhibitors of matrix metalloproteases and are therefore useful in treating or preventing conditions which involve tissue breakdown including rheumatoid arthritis and various diseases in which matrix metalloprotease activity is important. A number of small peptide-like compounds which inhibit collagenase are taught in U.S. Pat. No. 4,511,504. Aminobutanoic acid tripeptide inhibitors of metalloproteases are taught in EP 0 520 573 A1, published Jun. 23, 1992. Thiol based derivatives and hydroxamic acid based derivitives are taught in International Application WO 91/02716 published Mar. 7, 1991. Phosphonic acid derivatives are taught in International Application WO 91/15507 published Sep. 17, 1991. European Application EP O276 436 A1 published Aug. 3, 1988 teaches phosphinic acid derivatives as does European Application EP 0 236 872 A2 published Sep. 16, 1987.